Based on our previously published information, we have formulated an overall theoretical framework that these phenomena are the result of a morphine-induced alteration of protein(s) (enzyme) and/or a "receptor(s)" (lipid-protein complex probably associated wih the putative neurotransmitters). In order to test this investigative theory, we propose a multi-directional approach to the project but with the following objectives: (1) to determine if the effects of morphine on CA metabolism are indeed related to a modulation of morphine analgesia. (It seems necessary to further examine the effects of morphine or other narcotics on the synthesis, release and degradation of the CA and to further examine the effect of adrenergic agents, i.e., 6- OH-DA, MAOI, etc., on morphine analgesia). (2) To investigate possible sites, i.e., ribosome "amino acid activating process" and "transfer" reactions, RNA synthesis, DNA template activity of brain chromatin, where morphine could alter protein synthesis. Furthermore, we will investigate the possibility that morphine produces qualitative changes in protein synthesis due to the fact that morphine binds to brain polysome and consequently alters the "coding" system of mRNA which directs protein synthesis (miscoding due to morphine-polysome interaction). Preliminary results also call for investigation of the effect of morphine on some individual protein (enzyme), e.g., tyrosine hydroxylase, tryptophan hydroxylase, choline acetylase, adenyl cyclase, etc., which are known to be involved in the regulation of brain function via neurotransmitters. (3) To examine if the effects of morphine on the brain phospholipids (PI) are related to morphine induced changes in the biogenic amine function. (Special emphasis will be placed on phosphatidylcholine (PC) metabolism). (4) To clarify certain aspects of brain 5-HT metabolism which seem to be related to tolerance and physical dependence.